Mechanisms underlying anabolic effects of cyclic compressive loading in muscle

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The loss of skeletal muscle mass is a main contributor to disability in numerous disease states and is also a predictor of mortality and a major factor in the loss of independence in the elderly. We propose that massage is a novel intervention to attenuate acute muscle atrophy or aid with regrowth after muscle loss in patients who are unable to perform exercise. Massage is a manual therapy modality extensively used clinically for pain relief and as a modulator of immune responses; however, very few investigations have addressed the actual underlying mechanisms of the beneficial effects of massage, mainly because of the lack of consistency in the applied load. Using an innovative cyclic compressive loading (CCL) device for small rodents, mimicking massage with a well-defined load, we showed that CCL elevated protein synthesis when administered during disuse or recovery after atrophy, and enhanced the regrowth response in adult rats in the massaged limb, while no effect was seen in unperturbed or aged rats. Surprisingly, we also found a positive regrowth response in the contralateral, non-massaged limb. We suggest that protein synthesis is elevated through mechanosensitive anabolic pathways, such as the focal adhesion complexes including focal adhesion kinase (FAK) and integrin-linked kinase (ILK) in the massaged limb and that the growth effect in the non-massaged limb is mediated by a neuronal cross-over effect or by systemically-mediated mechanisms. These preliminary data led to following hypothesis: Massage, in the form of CCL, exerts an anabolic effect on muscle directly through mechanosensitive pathways, as well as indirectly by neurally or systemically mediated mechanisms, to enhance muscle size in perturbed growth states. We will use CCL in rats to study the muscle growth response using growth perturbations, i.e. disuse atrophy and regrowth after atrophy. In Aim 1 we will establish mechanisms for the attenuated growth response to CCL in muscles from aged compared to adult rats and test the hypothesis that muscles from aged rats show an attenuated response to CCL because of a stiffer extracellular matrix and a change in the pool of proteins synthesized. In Aim 2 the mechanosensitive pathways responsible for the growth response in skeletal muscle from adult rats after CCL will be investigated with particular attention to FAK and the role of satellite cells. In Aim 3 we will test the hypothesis that the increase in protein synthesis and muscle size in the contralateral non-massaged limb after CCL is due to a sensory feedback-regulated cross-over effect, but will also investigate systemic-mediated actions, such as cytokines and exosome-mediated transfer of miRNAs. Results from these studies will indicate whether massage is a viable intervention for preventing the loss of muscle mass during disuse or promoting regrowth of muscle after atrophy while determining the underlying mechanisms for the beneficial anabolic effects.